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Mechanisms of Toxicity in C. elegans Models of Transthyretin Amyloidosis

线虫运甲状腺素蛋白淀粉样变模型的毒性机制

基本信息

批准号：
9480905
负责人：
SANDRA E Encalada
金额：
$ 11.81万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-01 至 2021-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9480905
关键词：
Affect Age Aging Alpha Cell Amyloidosis Animal Model Antibodies Autonomic nervous system Axonal Transport Biochemical Biochemistry Biological Blood Caenorhabditis elegans Cardiomyopathies Cardiovascular Diagnostic Techniques Cells Cellular biology Complement Cytoskeleton Data Defect Degenerative Disorder Development Disease Dissociation Drosophila genus Elderly Exhibits Familial Amyloid Neuropathies Functional disorder Genetic Genetic Screening Heart Homeostasis Human Image Impairment Individual Link Liver Locomotion Longevity Maps Measures Messenger RNA Microtubules Mitochondria Mitotic Modeling Molecular Molecular Conformation Molecular Motors Molecular Target Morphology Mus Muscle Mutation Nerve Degeneration Neurodegenerative Disorders Neuroglia Neurons Neuropathy Organism Pathology Pathway interactions Patients Peripheral Peripheral Nervous System Diseases Pharmaceutical Preparations Phenotype Physiological Prealbumin Process Proteins RNA Interference Reporting Structure Synapses Testing Therapeutic Time Tissues Toxic effect Transgenic Organisms age related amyloidogenesis autonomic neuropathy base cytotoxicity experimental study extracellular forward genetics genome sequencing human disease improved in vivo monomer novel novel therapeutic intervention novel therapeutics protein aggregation proteotoxicity public health relevance small molecule tool trafficking whole genome

项目摘要

DESCRIPTION (provided by applicant): Protein aggregation is a feature of most neurodegenerative diseases, including the transthyretin (TTR) amyloidoses. TTR is a tetrameric protein secreted into the blood by the liver. Compelling evidence suggests that peripheral neurodegeneration in the TTR amyloidoses results from rate- limiting TTR tetramer dissociation, aberrant monomer misfolding and misfolded TTR assembly into a spectrum of TTR aggregate structures. Extracellular aggregation leads to proteotoxicity in tissues not synthesizing TTR by a cell non-autonomous process that we seek to understand via the proposed experiments, and which is not understood for any aggregation-associated neurodegenerative disease. In humans, WT TTR aggregation leads to a cardiomyopathy, whereas aggregation of other TTR mutations leads to a primary neuropathy. Herein, we report the development and partial characterization of transgenic Caenorhabditis elegans models of the TTR amyloidoses, exhibiting TTR aggregation and three cell non-autonomous quantifiable neuronal TTR proteotoxicity-associated cellular and sub-cellular phenotypes with direct relevance to human disease. We will characterize TTR mRNA levels and TTR conformations including tetramers, and misfolded TTR oligomers in these models as a function of aging and correlate these with the neuronal phenotypes observed. Defects in microtubule-based trafficking appear to be a centrally important mechanistic feature of TTR proteotoxicity. The availability of novel small molecule and genetic tools to quantify TTR conformation, as well as the ability to image sub-cellular phenotypes in a single neuron as a function of aging in the same living worm to quantify phenotypic changes affords us an extraordinary opportunity to understand the cell biology and biochemistry of neurodegeneration. Access to the drug tafamidis, which dramatically slows progression of the TTR amyloidoses in humans will also allow us to discern how inhibition of TTR aggregation alters the cell biological and biochemical defects apparently underlying neurodegeneration in these models. To further understand the mechanisms of TTR proteotoxicity at the cellular and molecular level, we will search for modulators of TTR proteotoxicity by identifying suppressors of a locomotion defect exhibited by one of our TTR models in a unbiased forward genetic screen. We have identified candidate suppressors in a pilot screen and showed that some exhibited proper TTR synthesis and secretion, suggesting that this screen could identify tissue specific molecular targets that are relays between the formation of extracellular TTR aggregates and cellular toxicity. These studies will establish TTR C. elegans models as relevant to the study of cell non-autonomous TTR toxicity.